Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations
Open accessAbstract
The accumulation of somatic mitochondrial DNA (mtDNA) mutations is implicated in aging and common diseases of the elderly, including cancer and neurodegenerative disease. However, the mechanisms that influence the frequency of somatic mtDNA mutations are poorly understood. To develop a simple invertebrate model system to address this matter, we used the Random Mutation Capture (RMC) assay to characterize the age-dependent frequency and distribution of mtDNA mutations in the fruit fly Drosophila melanogaster. Because oxidative stress is a major suspect in the age-dependent accumulation of somatic mtDNA mutations, we also used the RMC assay to explore the influence of oxidative stress on the somatic mtDNA mutation frequency. We found that many of the features associated with mtDNA mutations in vertebrates are conserved in Drosophila, including a comparable somatic mtDNA mutation frequency (∼10(-5)), an increased frequency of mtDNA mutations with age, and a prevalence of transition mutations. Only a small fraction of the mtDNA mutations detected in young or old animals were G∶C to T∶A transversions, a signature of oxidative damage, and loss-of-function mutations in the mitochondrial superoxide dismutase, Sod2, had no detectable influence on the somatic mtDNA mutation frequency. Moreover, a loss-of-function mutation in Ogg1, which encodes a DNA repair enzyme that removes oxidatively damaged deoxyguanosine residues (8-hydroxy-2'-deoxyguanosine), did not significantly influence the somatic mtDNA mutation frequency of Sod2 mutants. Together, these findings indicate that oxidative stress is not a major cause of somatic mtDNA mutations. Our data instead suggests that somatic mtDNA mutations arise primarily from errors that occur during mtDNA replication. Further studies using Drosophila should aid in the identification of factors that influence the frequency of somatic mtDNA mutations.
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G:C to T:A transversions are only a small fraction of the mutations found in aged Drosophila or humans.
“Conversely, G:C to T:A transversions are only a small fraction of the mutations found in aged Drosophila (Itsara et al., 2014) or humans (Kennedy et al., 2013; Zheng et al., 2006).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Itsara et al., 2014
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- Authors
- Itsara, L. S., Kennedy, S. R., Fox, E. J., Yu, S., Hewitt, J. J., Sanchez-Contreras, M., Cardozo-Pelaez, F., & Pallanck, L. J.
- Affiliations
- University of Washington (US)
- Corresponding author
- Pallanck, Leo J.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-02-06
- Volume
- 10
- Issue
- 2
- Pages
- e1003974
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3916223
- OpenAlex
- W2012998724
- Cited by
- 173
- References
- 67
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 6 · 2023: 7 · 2022: 20 · 2021: 11 · 2020: 18 · 2019: 16 · 2018: 15 · 2017: 18 · 2016: 15 · 2015: 19 · 2014: 7
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Muscular Dystrophy Association
- National Institute on Aging (T32AG000057, P01AG001751, AG013280, P30AG013280)
- National Cancer Institute
- National Institute of General Medical Sciences (R01GM104990, R01GM086394)
- National Institute of Neurological Disorders and Stroke (F31NS071857)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- somatic mitochondrial DNA mutations, oxidative stress, aging, Drosophila melanogaster, transition mutations, transversions, OGG1, DNA repair, 8-hydroxy-2'-deoxyguanosine
- MeSH terms
- Superoxide Dismutase 2, Aging, Animals, DNA Repair, DNA, Mitochondrial, Drosophila melanogaster, Humans, Mitochondria, Mutation, Superoxide Dismutase, Reactive Oxygen Species, Oxidative Stress, Models, Animal, Drosophila Proteins, DNA Glycosylases, Mutation Rate
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